Modulating t cell function and response

Abstract

The present disclosure describes a method of producing T cells exhibiting an enhanced memory T cell phenotype, the method comprising: modulating a population of T cells to enhance the expression and/or function of high mobility group protein Y (HMGY). In embodiments, the method may include introducing a polynucleotide encoding HMGY into a population of T cells, wherein expression of HMGY is higher in the population of T cells as compared to a population of T cells that are not introduced with the polynucleotide, and the memory T cell phenotype of the population of T cells is enhanced as compared to T cells that are not introduced with the polynucleotide. In embodiments, the method can also include introducing a polynucleotide encoding one or more genes associated with HMGY, for example, upstream or downstream of the signaling pathway associated with HMGY and/or a transcription factor associated with HMGY.

1 . A method of producing T cells exhibiting an enhanced memory T cell phenotype, the method comprising: introducing a polynucleotide encoding high-mobility group protein Y (HMGY) into a population of T cells, wherein expression of HMGY is higher in the population of T cells as compared to a population of T cells that are not introduced with the polynucleotide, and the memory T cell phenotype of the population of T cells is enhanced as compared to the population of T cells that are not introduced with the polynucleotide. 
     
     
         2 . The method of  claim 1 , wherein the population of T cells exhibits an increased gene expression level in CD62L and/or CCR7 as compared to a population of T cells that are not introduced with the polynucleotide. 
     
     
         3 . The method of  claim 1 , the method further comprising:
 obtaining peripheral blood mononuclear cells (PBMCs) from a subject or a healthy donor;   isolating the population of T cells from the PBMCs;   culturing the population of T cells; and   measuring expansion of the population of T cells.   
     
     
         4 . The method of  claim 3 , wherein expansion of the population of T cells is enhanced as compared to a population of T cells that are not introduced with the polynucleotide. 
     
     
         5 . The method of  claim 1 , the method further comprising:
 obtaining blood from a subject or a healthy donor, the blood comprising a population of T cells; and   introducing the polynucleotide encoding HMGY into the blood.   
     
     
         6 . The method of  claim 1 , wherein the polynucleotide comprises SEQ ID NO: 61 or SEQ ID NOS: 61and 63. 
     
     
         7 . The method of  claim 1 , the method further comprising contacting the population of T cells with an antigen that the population of T cells bind. 
     
     
         8 . The method of  claim 7 , wherein the population of T cells exhibits a reduced gene expression level of CD137 and/or KLRG as compared to a population of T cells that are not introduced with the polynucleotide. 
     
     
         9 . The method of  claim 1 , wherein the population of T cells comprising enhanced memory T cell phenotype comprises an increased gene expression level of CD62L and/or CCR7 as compared to a population of T cells that are not introduced with the polynucleotide. 
     
     
         10 . The method of  claim 1 , wherein the population of T cells comprising enhanced memory T cell phenotype comprises a reduced gene expression level of CD137 and/or KLRG as compared to a population of T cells that are not introduced with the polynucleotide. 
     
     
         11 . The method of  claim 1 , wherein the population of T cells comprise an antigen binding molecule. 
     
     
         12 . The method of  claim 11 , wherein the antigen binding molecule is a chimeric antigen receptor (CAR), which comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. 
     
     
         13 . The method of  claim 12 , wherein the antigen binding domain binds a tumor antigen selected from a group consisting of TSHR, CD19, CD123, CD22, CD30, CD171, CS-1, CLL-1, CD33, EGFRvIII, GD2, GD3, BCMA, Tn Ag, PSMA, ROR1, FLT3, FAP, TAG72, CD38, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, Mesothelin, IL-11Ra, PSCA, PRSS21, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, CD20, Folate receptor alpha, ERBB2 (Her2/neu), MUC1, EGFR, NCAM, Prostase, PAP, ELF2M, Ephrin B2, IGF-I receptor, CAIX, LMP2, gp100, bcr-abl, tyrosinase, EphA2, Fucosyl GM1, sLe, GM3, TGS5, HMWMAA, o-acetyl-GD2, Folate receptor beta, TEM1/CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, Polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TARP, WT1, NY-ESO-1, LACE-1a, MAGE-A1, legumain, HPV E6, E7, MAGE A1, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, p53, p53 mutant, prostein, survivin, telomerase, PCTA-1/Galectin 8, MelanA/MART1, Ras mutant, hTERT, sarcoma translocation breakpoints, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, Androgen receptor, Cyclin 61, MYCN, RhoC, TRP-2, CYP161, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxyl esterase, mut hsp70-2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, and IGLL1. 
     
     
         14 . The method of  claim 12 , wherein the intracellular signaling domain comprises a co-stimulatory signaling domain, or a primary signaling domain and a co-stimulatory signaling domain, wherein the co-stimulatory signaling domain comprises a functional signaling domain of a protein selected from the group consisting of CD27, CD28, 4-166 (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, NKp44, NKp30, NKp46, and NKG2D. 
     
     
         15 . The method of  claim 11 , wherein the antigen binding molecule is a modified TCR. 
     
     
         16 . The method of  claim 15 , wherein the TCR is derived from spontaneously occurring tumor-specific T cells in patients. 
     
     
         17 . The method of  claim 16 , wherein the TCR binds a tumor antigen. 
     
     
         18 . The method of  claim 17 , wherein the tumor antigen comprises CEA, gp100, MART-1, p53, MAGE-A3, or NY-ESO-1. 
     
     
         19 . The method of  claim 18 , wherein the TCR comprises TCRγ and TCRδ chains, TCRα and TCRβ chains, or a combination thereof. 
     
     
         20 . The method of  claim 1 , wherein the cell is a human cell.